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Previously an increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), was reported among Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dysregulated expression of certain microRNAs (miRNAs) was demonstrated in MGUS and MM. Given the important role of miRNAs in cellular homeostasis, the aim of this study was to determine if there was an association between serum levels of selected miRNAs and TCDD in 47 MGUS cases identified in our previous investigation using serum specimens and exposure data archived by the Air Force Health Study (AFHS). A total of 13 miRNA levels (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335, and miR-361) was measured in serum stored during the 2002 AFHS follow-up and the relationship to lipid-adjusted serum TCDD levels in 1987 was determined. miR-34a showed the strongest relationship with TCDD; after age-adjustment, this positive association was more pronounced. In contrast, the other 12 miRNAs displayed absolute values of age adjusted coefficient estimates below 1.16 and non-significant p-values. The observed strong positive association between high body burdens of TCDD and miR-34a, a tumor suppressor regulated by p53, in this MGUS population warrants clarification of the TCDD-miR-34a relationship and its role in the pathogenesis of MGUS and risk for MM. [ABSTRACT FROM AUTHOR]

The aryl hydrocarbon receptor (AHR) plays a major role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity phenotypes. TCDD bound to AHR elicits both genomic action in which target genes are transcriptionally upregulated and nongenomic action in which cytosolic phospholipase A2α (cPLA2α) is rapidly activated. However, how either of these actions, separately or in combination, induces toxicity phenotypes is largely unknown. In this study, we used AHRnls/nls mice as a model in which AHR was mutated to lack nuclear translocation sequence (NLS), and AHRd/− mice as the corresponding control. Using this model, we studied TCDD-induced alterations in cPLA2α activation and related factors because of the pivotal roles of cPLA2α both in AHR's nongenomic action and in regulation of causative genes of TCDD-induced hydronephrosis. Dams were orally administered TCDD at a dose of 300 µg/kg body weight on postnatal day 1, and pups subsequently exposed to TCDD via milk were examined for gene expression on PND 7 and for histological changes on PND 14. The activation of the AHR genomic action and hydronephrosis onset were observed in the control group but not in the AHRnls/nls group. An ex vivo experiment using peritoneal macrophages exposed to 100 nM TCDD resulted in rapid activation of cPLA2α, an indicator of the nongenomic action, only in the control group but not in the AHRnls/nls group. These results indicated that an NLS is required for the AHR's genomic and nongenomic actions. [ABSTRACT FROM AUTHOR]

Abstract Background Persistent organic pollutants (POPs) are known to accumulate in adipose tissues (AT). This storage may be beneficial by diverting POPs from other sensitive tissues or detrimental because of chronic release of pollutants as indirectly suggested during weight loss. The aim is to study the biological and/or toxic effects that chronic POP release from previously contaminated grafted AT could exert in a naïve mouse. Methods C57BL/6J male mice were exposed intraperitoneally to 2,3,7,8-tetrachlorodibenzo- p -doxin (TCDD); their epididymal fat pads were collected and grafted on the back skin of uncontaminated recipient mice whose brain, liver, and epididymal ATs were analyzed (TCDD concentration, relevant gene expression). Kinetics of release and redistribution were modeled using Physiologically Based PharmacoKinetics (PBPK). Results The grafts released TCDD over a period of 10 weeks with different kinetics of distribution in the three organs studied. A PBPK model was used to simulate the AT releasing process and the incorporation of TCDD into the major organs. At three weeks post-graft, we observed significant changes in gene expression in the liver and the host AT with signatures reminiscent of inflammation, gluconeogenesis and fibrosis as compared to the control. Conclusions This study confirms that AT-stored TCDD can be released and distributed to the organs of the recipient hence leading to distinct changes in gene expression. This original model provides direct evidence of the potential toxic-relevant effects when endogenous sources of contamination are present. Highlights • A new model to study the release and distribution of POPs • Introduction of a new PBPK model to study the effects of POPs • Internal release of TCDD activates signatures of inflammation & fibrosis. • Internal stores of POPs could play a significant role in long term toxicity. [ABSTRACT FROM AUTHOR]

Bien Hoa airbase is located in Dong Nai Province (Southern Vietnam). Several sites within the airbase are highly contaminated by Agent Orange/Dioxin, and thus, they are also commonly named as an Agent Orange/Dioxin hotpot. In the present study, 36 maternal milk samples were collected from primiparas who have lived at least 5 years in four wards, Buu Long, Quang Vinh, Trung Dung and Tan Phong, which are closed to Bien Hoa airbase in order to investigate the level and distribution of Agent Orange/Dioxin exposure in different local communities. The mean concentrations of PCDD/PCDFs in four investigated wards range from 6.4 to 13.6 pgTEQ/g lipid. The highest mean TEQ of PCDD/PCDFs was observed in Buu Long ward (13.6 pgTEQ/g lipid), followed by Tan Phong ward (12.3 pgTEQ/g lipid), and the lowest value was observed in Trung Dung ward (6.4 pgTEQ/g lipid). The mean concentration of 2,3,7,8-TCDD in Buu Long (7.6 pg/g lipid) was approximately 2-6 times higher than those in Tan Phong (3.9 pg/g lipid), Quang Vinh (2.3 pg/g lipid), or Trung Dung (1.2 pg/g lipid). These results imply site-specific exposure to PCDD/PCDFs in different local communities living around Bien Hoa airbase. The mean values of daily intake of dioxin estimated for the breast fed infants living in Buu Long, Quang Vinh, Trung Dung and Tan Phong were about 80, 37.5, 31.7 and 58 pg TEQ/kg bw/day, respectively. [ABSTRACT FROM AUTHOR]

Purpose Patients with Yusho, a condition caused by exposure to dioxins and dioxin-like compounds, have diverse mental and physical complaints. However, the relationship between dioxins and sleep disorders has not yet been examined. This cross-sectional study was designed to investigate problems associated with sleep among patients with Yusho. Methods A total of 140 participants (52.9% men, average age: 67.1 ± 12.2 years) were examined using questionnaires and medical interviews by an expert on sleep medicine. Demographic and clinical characteristics, including blood concentrations of 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), which is the major cause of Yusho, were obtained from the results of recent surveys conducted by the Yusho Study Group. Results Moderate to severe symptoms of insomnia were present in 51.8% of the patients. The median Pittsburgh Sleep Quality Index global score (PSQI GS) was 8 (interquartile range: 5–11). The prevalence of restless legs syndrome/Willis–Ekbom disease (RLS/WED) was 30.7%; 24.3% of patients had severe RLS/WED (distressing symptoms with a frequency ≥ 1day per week). A higher blood concentration of 2,3,4,7,8-PeCDF (≥72.27 pg/g lipid) and severe RLS/WED were associated with higher odds of a PSQI GS ≥8, after adjusting for covariates (odds ratio [95% confidence interval]: 4.84 [1.10–21.25] and 4.15 [1.53–11.28], respectively). Conclusions Symptoms of insomnia were frequent, and the prevalence of RLS/WED was high in patients with Yusho. In addition to the presence of RLS/WED, a higher blood concentration of 2,3,4,7,8-PeCDF was associated with lower subjective sleep quality. [ABSTRACT FROM AUTHOR]

We have previously reported that a cell-free extract prepared from Geobacillus thermodenitrificans UZO 3 reductively cleaves diaryl ether bonds of 2,3,7,8-tetrachlorodibenzo- p -dioxin (2,3,7,8-TCDD), a dioxin with the highest toxicity, in a sequential fashion producing 3′,4′,4,5-tetrachloro-2-hydroxydiphenyl ether (TCDE) as the intermediate, and 3,4-dichlorophenol (DCP) as the final reaction product. The detection of TCDE implicated the discovery of an unprecedented dioxin-degrading enzyme that reductively cleaves the diaryl ether bonds. In this study, we report the cloning and sequencing of the dioxin reductive etherase gene dreE which codes for the 2,3,7,8-TCDD-degrading enzyme. We showed that dreE was expressed in Escherichia coli and that the product of the expression could reductively cleave diaryl ether bonds of 2,3,7,8-TCDD to produce TCDE. Furthermore, we established that the amino acid sequence encoded by dreE was homologous to an enzyme with yet unknown function that is encoded by a gene located in the riboflavin (vitamin B2) biosynthesis operon in Bacillus subtilis. We also showed that the amino acid sequence possesses a coenzyme A (CoA) binding site that is conserved in the N-acyltransferase superfamily. For the first time, the degradation of 2,3,7,8-TCDD at the molecular level using a enzyme of bacterial origin has been demonstrated. A novel mechanism model for the reductive cleavage of diaryl ether bond of 2,3,7,8-TCDD was also proposed. [ABSTRACT FROM AUTHOR]

Dioxin is a highly toxic and caustic substance, which widely existed in the atmosphere, soil and water with tiny particles. Dioxin pollution has become a major problem that concerns the survival of mankind, which must be strictly controlled. The bond length, bond angle, energy, dipole moment, orbital energy level distribution of dioxin under the external field are investigated using DFT (density functional theory) on basis set level of B3LYP/6-31G (d, p). The results indicate that with the increase of the electric field, the length of one Carbon-Oxygen bond increases while another Carbon-Oxygen bond decreases. The energy gradually decreases with the electric field, while the change of the dipole moment has an opposite trend. In the infrared spectra, the vibration frequency decreases with the electric field increasing and shows an obvious red shift. Moreover, the ultraviolet-visible absorption spectra under different electric fields are analyzed with TD-DFT (time-dependent density functional theory) method. The wavelength of the strongest absorption peak increases and occurs red shift with the increase of the electric field. All the above results can provide reference for further research on the properties of dioxin under different external electric field. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD), the classic aryl hydrocarbon receptor (AhR) agonist, is a potent environmental toxicant and endocrine-disrupting chemical (EDC) with known developmental toxicity in humans, rodents, and fish. Early life exposure to some EDCs, including TCDD, is linked to the occurrence of adult-onset and multigenerational disease. Previous work exposing juvenile F0 zebrafish (Danio rerio) to 50 ppt (parts per trillion) TCDD during reproductive development has shown male-mediated transgenerational decreases in fertility (F0–F2) and histologic and transcriptomic alterations in F0 testes. Here, we analyzed male germline alterations in F1 and F2 adult fish, looking for changes in testicular histology and gene expression inherited through the male lineage that could account for decreased reproductive capacity. Testes of TCDD-lineage F1 fish displayed an increase in spermatogonia (immature germ cells) and decrease in spermatozoa (mature germ cells). No histological changes were present in F2 fish. Transcriptomic analysis of exposed F1 and F2 testes revealed alterations in lipid and glucose metabolism, oxidation, xenobiotic response, and sperm cell development and maintenance genes, all of which are implicated in fertility outcomes. Overall, we found that differential expression of reproductive genes and reduced capacity of sperm cells to mature could account for the reproductive defects previously seen in TCDD-exposed male zebrafish and their descendants, providing insight into the distinct multigenerational effects of toxicant exposure. [ABSTRACT FROM AUTHOR]

Open combustion of solid waste is one of the main sources of the emission of dioxin and dioxin-like compounds (DLCs). Ambient dioxin will eventually undergo depositions on soils and tree leaves. Pine trees have shown an ability to store dioxin in their needles allowing biomonitoring of dioxin atmospheric concentrations. Infiltration can transport dioxin to greater depths into the ground, on one hand, while vaporization can allow dioxin to return back to the atmosphere on the other. Several studies evaluated the migration of dioxin between two compartments; however, few studies have attempted to understand the fate of non-conservative PCDDs and PCDFs in an unsteady state system of more than two mediums. This study focused on the transportation of dioxin between polluted trees and the underlying soil through the effect of rain water. For approximately 10 years, pine trees in this study have been exposed to emissions generated by the open combustion of municipal solid waste (MSW) from a fixed location. Soil samples located further from the point source had generally lower dioxin concentrations. Dioxin concentrations were correlated to distance from the source using least square regression. Soil samples below contaminated trees had dioxin concentrations 10-35% greater than the calculated measurements for the same spots using the regression model. By detecting these spikes in concentrations, it was possible to identify pools of dioxin found directly under the contaminated trees—indicating a rinsing effect of rain water on the stored dioxin on the trees’ needles. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a reproductive and developmental toxicant that can alter the sex ratio of offspring (proportion of male offspring). We hypothesized that the alteration of sex ratio is associated with sex chromosome ratio of live spermatozoa affected by exposure to TCDD. After exposure to TCDD we analyzed simultaneously sperm sex chromosome constitution and viability, and evaluated sperm sex chromosome ratio association with embryo sex ratio in mice. Short-term exposure to TCDD affects the decreased sperm motility and viability, and the increased acrosome reaction. Interestingly, Y spermatozoa survived shorter than X spermatozoa at high concentrations of TCDD. Moreover, the decreased sex ratio of embryos was associated with the short lifespan of Y spermatozoa. Our results suggest that TCDD may affect the fertility of Y spermatozoa more than X spermatozoa. Further studies are needed to compare the difference of fertilizing capability between X and Y spermatozoa by the effect of TCDD. [ABSTRACT FROM AUTHOR]

Dioxins are highly toxic persistent organic pollutants bioaccumulated by both plants and animals that cause severe developmental abnormalities in humans. We investigated the effects of dioxins on seed development in Arabidopsis. Plants were exposed to various concentrations of the most toxic congener of dioxins, 2,3,7,8-tetrachlorodibenzop- dioxin (TCDD) and the effects on seed development were analysed in-depth at transcriptome, proteome and metabolome levels. Exposure to dioxin led to generalized effects on vegetative tissues plus a specific set of perturbations to seed development. Mature seeds from TCDD-treated plants had a characteristic 'wrinkled' phenotype, due to a two-thirds reduction in storage oil content. Transcriptional analysis of a panel of genes related to lipid and carbohydrate metabolism was consistent with the observed biochemical phenotypes. There were increases in WRI1 and LEC1 expression but decreases in ABI3 and FUS3 expression, which is puzzling in view of the low seed oil phenotype. This anomaly was explained by increased expression of 20S proteasome components that resulted in a substantial degradation of WRI1 protein, despite the up-regulation of the WRI1 gene. Our findings reveal novel effects of dioxins that lead to altered gene regulation patterns that profoundly affect seed development in Arabidopsis. [ABSTRACT FROM AUTHOR]

2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) is an environmental contaminant and its toxicity is mediated by the aryl hydrocarbon receptor (AHR). Mechanisms of TCDD cardiovascular toxicity consist of oxidative stress, growth factor modulation, and ionic current alteration. It is indicated that the rodent cardiovascular system is a target for TCDD cardiomyopathy. Here, our understanding of TCDD cardiovascular toxicity is reviewed. [ABSTRACT FROM AUTHOR]

Dioxins and dioxin-like compounds can be analyzed by bioanalytical screening methods to evaluate their biotoxicity. In vitro bioassays, based on 7-ethoxyresorufin-O-deethylase (EROD) and the activity of cytochrome P450 1A1 and the aryl hydrogen receptor (AhR) pathway, are employed for the evaluation of bioanalytical equivalents (BEQ) of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) from a wide variety of sample matrices. Here, we present the evaluation of 11 humic soil samples derived from forest stands across Germany and a comparison of the BEQ values against toxic equivalents (TEQ, PCDD/Fs+PCBs) derived by chemical analysis. BEQ values ranged from 8.8 to 34.1 while TEQ values from 13.9 to 60.5 pg/g dry weight. Additional two subsequent mineral layers were analyzed to identify the BEQ/TEQ gradient vertically, showing a TEQ decrease of 85.1 and 93.8 % from the humic to the first and second mineral layers, respectively. For BEQ values, a decrease as well as an increase was detected. BEQ measurements were performed with and without sample clean-up. Omitting clean-up revealed about 20 times increased BEQ values presumably due to non-persistent bioactive compounds not detected by chemical analysis. The results we present suggest that the EROD assay can be used for the screening of large sample quantities for the identification of samples showing dioxin and dioxin-like contaminations even at low levels, which can then be further analyzed by chemical analysis to identify the congener composition. The study also shows that EROD results give a qualitative image of the contamination. EROD seems to be interfered with cross-contaminants specifically for soils with high biological activity as forest layers. [ABSTRACT FROM AUTHOR]

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces a variety of toxicities upon binding of TCDD to aryl hydrocarbon receptor. Although this binding upregulates the synthesis of prostaglandins and their related lipid mediators via cytosolic phospholipase A2α (cPLA2α), toxicological significance of this signaling pathway remains elusive. Herein, we investigated the roles of cPLA2α in TCDD toxicities using cPLA2α-null mice. In a first set of experiments, pregnant mice were orally administered TCDD at a dose of 40 μg/kg on gestation day (GD) 12.5, and fetuses were collected on GD 18 for subsequent analyses. The number of live male fetuses of cPLA2α-null type was significantly less than that of wild-type in TCDD-exposed litters. TCDD-induced hydronephrosis was more severe in wild-type fetuses than in cPLA2α-null fetuses regardless of sex, and kidney expression levels of the inflammatory cytokines interleukin-1β and tumor necrosis factor-α were increased in a cPLA2α-dependent manner in TCDD-exposed fetuses. In a second set of experiments, following intraperitoneal administration of TCDD at 50 μg/kg, body weight of the male adult mice was decreased within 2 days in wild-type mice but was not changed in cPLA2α-null mice. In addition, TCDD-induced lipid accumulation in the livers of cPLA2α-null mice was at an intermediate level compared with TCDD-exposed wild-type and vehicle-control mice. In conclusion, the present results show that cPLA2α is involved in TCDD-induced body weight loss, lipid accumulation in the liver, fetal hydronephrosis, and cytokine gene expression, and that the molecular basis of TCDD toxicity differs considerably between target tissues and life stages. [ABSTRACT FROM AUTHOR]

Objectives To conduct a cross-sectional morbidity survey among 245 former employees of a pesticide production plant exposed to 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) in New Zealand. Methods Demographic factors and health information were collected in face-to-face interviews. TCDD, lipids, thyroid hormones, glucose and immunoglobulin G (IgG) were determined in non-fasting blood. For 111 participants, a neurological examination was conducted. Associations between health outcomes and working in a TCDD exposed job (prevalence 49%) and serum TCDD concentration ≥ 10 pg/g lipid (18%) were assessed using logistic regression whilst controlling for age, gender, smoking, body mass index and ethnicity. Results Diabetes was more common in those who had worked in TCDD exposed jobs (OR 4.0, 95%CI 1.0–15.4) and in those with serum TCDD ≥ 10 pg/g (OR 3.1, 95%CI 0.9–10.7). Non-fasting glucose levels > 6.6 mmol/l were more common in those with TCDD exposed jobs (OR 3.6, 95%CI 1.0–12.9), as were serum free thyroxine 4 < 12.8 pmol/l (OR 4.5, 95%CI 1.4–14.4), triglycerides > 1.7 mmol/l (OR 2.5, 95%CI 1.1–5.7) and high density lipoprotein cholesterol (HDL) < 1 mmol/l (OR 4.0, 95%CI 1.2–13.2). IgG was negatively associated with TCDD (linear regression p = 0.05). The neurological examination revealed a higher frequency of abnormal reflexes in those with serum TCDD ≥ 10 pg/g (OR 4.8, 95%CI 1.1–21.0). Conclusions In this occupationally exposed population, TCDD was associated with an increased risk of diabetes and a range of subclinical responses in multiple systems (peripheral nervous system, immune system, thyroid hormones and lipid metabolism), several decades after last exposure. These results need to be interpreted with caution due to the small study size and the cross-sectional nature of the study. [ABSTRACT FROM AUTHOR]

Over the past decades, southern Vietnam has been burdened by dioxins from contaminated herbicides sprayed during the Vietnam War. In a previous study, we found that dioxin exposure decreased levels of salivary dehydroepiandrosterone (DHEA), an adrenal androgen, in 3-year-old children. In present study, to assess the relationship between adrenal hormones disruption in lactating mothers and in children, we compared mother-child pairs from dioxin- and nondioxin-contaminated regions. In 2010 and 2011, mother-child pairs from a dioxin hotspot region (n = 37) and a non-contaminated region (n = 47) were recruited and donated breast milk and serum samples for dioxin and steroid hormones determination. Mothers were 20–30 years old and had given birth to their first child between 4 and 16 weeks previously. One year later, saliva samples were collected from the children. Dioxin levels in breast milk were determined by gas chromatography/high-resolution mass spectrometry. Salivary DHEA, cortisol in children and androstenedione (A-dione), estradiol, cortisol, and DHEA in maternal serum were analyzed by liquid chromatography/tandem mass spectrometry. Concentrations of dioxin congeners in the hotspot region were 2- to 5-fold higher than in samples from the non-contaminated region. Salivary DHEA levels in children and serum A-dione levels in mothers were significantly higher in the hotspot region; no difference was found in the levels of other hormones. Moreover, there was a significant positive correlation between the elevated hormone levels in mothers and children (r = 0.62, p < 0.001). Several dioxin congeners exhibited strong significant dose-response relationships with salivary DHEA and serum A-dione levels. Our findings suggest that dioxin disrupts adrenal androgens in mothers and breastfeeding children through the same mechanism. [ABSTRACT FROM AUTHOR]

Significant prolonged aryl hydrocarbon receptor (AHR) activation, classically exhibited following exposure to 2,3,7,8- tetrachlorodibenzo-p-dioxin, can cause a variety of undesirable toxicological effects. Novel pharmaceutical chemistries also have the potential to cause activation of AHR and consequent toxicities in pre-clinical species and man. Previous methods either employed relatively expensive and low-throughput primary hepatocyte dosing with PCR endpoint, or low resolution overexpressing reporter gene assays. We have developed, validated and applied an in vitro microtitre plate imaging-based medium throughput screening assay for the assessment of endogenous species-specific AHR activation potential via detection of induction of the surrogate transcriptional target Cytochrome P450 CYP1A1. Routine testing of pharmaceutical drug development candidate chemistries using this assay can influence the chemical design process and highlight AHR liabilities. This assay should be introduced such that human AHR activation liability is flagged early for confirmatory testing. [ABSTRACT FROM AUTHOR]

We have previously shown that cytochrome P450 1A1 (CYP1A1) was highly induced for a long period of time in a patient who had been poisoned by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound known to activate the aryl hydrocarbon receptor (AhR). During that period of time, no sebaceous glands could be observed in the skin of this patient. In this study, starting from observations in the patient exposed to TCDD, we analyzed the seboatrophy induced by dioxins in mice. We observed a very different pattern of AhR and CYP1A1 immunostaining in skin biopsies of the patient. When applying TCDD and beta-naphthoflavone, another AhR agonist, on the ears of C57BL/6J mice, we reproduced (1) an atrophy of sebaceous glands, (2) a strong induction of CYP1A1 within the glands, and (3) a dramatic repression of the genes encoding the sebogenic enzymes AWAT1, ELOVL3, and SCD1. These effects were reversible. Leucine-rich repeats and immunoglobulinlike domains protein 1 (LRIG1) expressing progenitor cells, found in the vicinity of sebaceous glands, were shown to be the initial skin cellular targets of AhR agonists. These cells retained the DNA label BrdU and colocalized with the CYP1A1 protein for at least 30 days. A downregulation of LRIG1 by siRNA in cultured sebocytes significantly decreased the CYP1A1 response to TCDD, indicating that LRIG1 contributes to a higher susceptibility of AhR agonists. In conclusion, these observations provide for the first time a strong experimental support to the concept that dioxin-induced skin pathology may be driven by a molecular switch in progenitor cells involved in the physiological turnover of sebaceous glands. [ABSTRACT FROM AUTHOR]

Endothelial injury or dysfunction is an early event in the pathogenesis of atherosclerosis. Epidemiological and animal studies have shown that 2, 3, 7, 8-tetrachlorodibenzo- p-dioxin (TCDD) exposure increases morbidity and mortality from chronic cardiovascular diseases, including atherosclerosis. However, whether or how TCDD exposure causes endothelial injury or dysfunction remains largely unknown. Cultured human umbilical vein endothelial cells (HUVECs) were exposed to different doses of TCDD, and cell apoptosis was examined. We found that TCDD treatment increased caspase 3 activity and apoptosis in HUVECs in a dose-dependent manner,at doses from 10 to 40 nM. TCDD increased cyclooxygenase enzymes (COX)-2 expression and its downstream prostaglandin (PG) production (mainly PGE2 and 6-keto-PGF1α) in HUVECs. Interestingly, inhibition of COX-2, but not COX-1, markedly attenuated TCDD-triggered apoptosis in HUVECs. Pharmacological inhibition or gene silencing of the PGE2 receptor subtype 3 (EP3) suppressed the augmented apoptosis in TCDD-treated HUVECs. Activation of the EP3 receptor enhanced p38 MAPK phosphorylation and decreased Bcl-2 expression following TCDD treatment. Both p38 MAPK suppression and Bcl-2 overexpression attenuated the apoptosis in TCDD-treated HUVECs. TCDD increased EP3-dependent Rho activity and subsequently promoted p38MAPK/Bcl-2 pathway-mediated apoptosis in HUVECs. In addition, TCDD promoted apoptosis in vascular endothelium and delayed re-endothelialization after femoral artery injury in wild-type (WT) mice, but not in EP3−/− mice. In summary, TCDD promotes endothelial apoptosis through the COX-2/PGE2/EP3/p38MAPK/Bcl-2 pathway. Given the cardiovascular hazard of a COX-2 inhibitor, our findings indicate that the EP3 receptor and its downstream pathways may be potential targets for prevention of TCDD-associated cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Analyses were conducted of reproductive outcomes for conceptions of participants of the Air Force Heath Study. Participants were male Air Force veterans of the Vietnam War. Conceptions were categorized into conceived before and after the start of the participant's Vietnam War service. Analyses accounted for correlation between outcomes for multiple conceptions for each participant. For each of three non-sparsely occurring outcomes, including not live born, miscarriage, and preterm, the probability of occurrence increased substantially when conceived after compared to before the start of Vietnam War service. These results support the conclusion of an adverse effect due to Vietnam War service on these reproductive outcomes. Data for conceptions after the start of Vietnam War service for participants with measured dioxin values were used to estimate dose-response curves for the effect of dioxin exposure on the occurrence of each of the three non-sparsely occurring outcomes. These curves were assumed to be constant up to a threshold and then monotonic after that threshold. For each of the three non-sparsely occurring outcomes, the estimated dose-response curves increased nonlinearly after associated thresholds. These results support the conclusion that the adverse effect due to conception after the start of Vietnam War service is attributable to high enough exposures to dioxin, a toxic contaminant of Agent Orange used for herbicide spraying in the Vietnam War. Sensitivity analyses supported the conclusion that dioxin results were not substantially affected by the assumption of monotonicity, decay due to elapsed time from exposure to measurement, and available covariates. • Vietnam service adversely affected reproductive outcomes for male veterans. • Adverse effects were attributable to increased dioxin exposures. • Results held for occurrence of not live born, miscarriage, and preterm conceptions. • Adverse effects for participants with measured dioxin likely hold more generally. • A variety of limitations may have affected these conclusions. [ABSTRACT FROM AUTHOR]

Activated carbon (AC) is an increasingly attractive remediation alternative for the sequestration of dioxins at contaminated sites globally. However, the potential for AC to reduce the bioavailability of dioxins in mammals and the residing gut microbiota has received less attention. This question was partially answered in a recent study examining 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)-induced hallmark toxic responses in mice administered with TCDD sequestered by AC or freely available in corn oil by oral gavage. Results from that study support the use of AC to significantly reduce the bioavailability of TCDD to the host. Herein, we examined the bioavailability of TCDD sequestered to AC on a key murine gut commensal and the influence of AC on the community structure of the gut microbiota. The analysis included qPCR to quantify the expression of segmented filamentous bacteria (SFB) in the mouse ileum, which has responded to TCDD-induced host toxicity in previous studies and community structure via sequencing the 16S ribosomal RNA (rRNA) gene. The expression of SFB 16S rRNA gene and functional genes significantly increased with TCDD administered with corn oil vehicle. Such a response was absent when TCDD was sequestered by AC. In addition, AC appeared to have a minimal influence on murine gut community structure and diversity, affecting only the relative abundance of Lactobacillaceae and two other groups. Results of this study further support the remedial use of AC for eliminating bioavailability of TCDD to host and subsequent influence on the gut microbiome. [ABSTRACT FROM AUTHOR]

Our previous studies demonstrated that treating pregnant rats with dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), targets the pituitary expression of luteinizing hormone (LH) to attenuate testicular steroidogenesis in fetuses, resulting in the imprinting of sexual immaturity of the offspring after reaching maturity. Furthermore, we found that although TCDD disturbs the tricarboxylic acid (TCA) cycle in the fetal hypothalamus, maternal co-treatment with a-lipoic acid (α-LA), a cofactor of the TCA cycle, restores a TCDD-produced reduction in the LH-evoked steroidogenesis as well as the TCA cycle activity in fetuses. However, the mechanism underlying the beneficial effect of α-LA remains to be fully elucidated. To address this issue, we compared the effect of α-LA with that of thiamine, another cofactor of the TCA cycle. As with α-LA, supplying thiamine to dams exposed to TCDD alleviates the reduced level of not only hypothalamic ATP but also pituitary LH and testicular steroidogenic protein in fetuses. However, thiamine had a much weaker effect than α-LA. In agreement with ATP attenuation, TCDD activated AMP-activated protein kinase (AMPK), a negative regulator of LH production, whereas the supplementation of α-LA allowed recovery from this defect. Furthermore, α-LA restored the TCDD-produced reduction in the pituitary expression of the receptor for gonadotropin-releasing hormone (GnRH), an upstream regulator of LH synthesis. These results suggest that α-LA rescues TCDD-produced attenuation during fetal steroidogenesis due not only to facilitation of energy production through the TCA cycle but also through suppression of AMPK activation, and the pituitary GnRH receptor may serve as a mediator of these effects. [ABSTRACT FROM AUTHOR]

The mechanisms by which pollutants participate in the development of diverse pathologies are not completely understood. The pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) activates the AhR (aryl hydrocarbon receptor) signaling pathway. We previously showed that TCDD (25 nM, 30 h) decreased the expression of several alcohol metabolism enzymes (cytochrome P450 2E1, alcohol dehydrogenases ADH1, 4 and 6) in differentiated human hepatic cells (HepaRG). Here, we show that, as rapidly as 8 h after treatment (25 nM TCDD) ADH expression decreased 40 % ( p < 0.05). ADH1 and 4 protein levels decreased 40 and 27 %, respectively ( p < 0.05), after 72 h (25 nM TCDD). The protein half-lives were not modified by TCDD which suggests transcriptional regulation of expression. The AhR antagonist CH-223191 or AhR siRNA reduced the inhibitory effect of 25 nM TCDD on ADH1A, 4 and 6 expression 50-100 % ( p < 0.05). The genomic pathway (via the AhR/ARNT complex) and not the non-genomic pathway involving c-SRC mediated these effects. Other AhR ligands (3-methylcholanthrene and PCB 126) decreased ADH1B, 4 and 6 mRNAs by more than 78 and 55 %, respectively ( p < 0.01). TCDD also regulated the expression of ADH4 in the HepG2 human hepatic cell line, in primary human hepatocytes and in C57BL/6J mouse liver. In conclusion, activation of the AhR/ARNT signaling pathway by AhR ligands represents a novel mechanism for regulating the expression of ADHs. These effects may be implicated in the toxicity of AhR ligands as well as in the alteration of ethanol or retinol metabolism and may be associated further with higher risk of liver diseases or/and alcohol abuse disorders. [ABSTRACT FROM AUTHOR]

Analyses were conducted of the occurrence of eight general categories of birth defects and developmental disabilities for children fathered by participants of the Air Force Heath Study (AFHS). Participants were male Air Force veterans of the Vietnam War. Children were categorized into conceived before and after the start of the participant's Vietnam War service. Analyses accounted for correlation between outcomes for multiple children fathered by each of the participants. For each of the eight general categories of birth defects and developmental disabilities, the probability of its occurrence increased substantially for children conceived after compared to before the start of Vietnam War service. These results support the conclusion of an adverse effect on reproductive outcomes due to Vietnam War service. Data for children conceived after the start of Vietnam War service for participants with measured dioxin values were used to estimate dose-response curves for the effect of dioxin exposure on the occurrence of each of the eight general categories of birth defects and developmental disabilities. These curves were assumed to be constant up to a threshold and then monotonic after that threshold. For seven of the eight general categories of birth defects and developmental disabilities, the estimated dose-response curves increased nonlinearly after associated thresholds. These results support the conclusion that the adverse effect to conception after the start of Vietnam War service may be attributable to high enough exposures to dioxin, a toxic contaminant of Agent Orange used for herbicide spraying in the Vietnam War. • Vietnam service may have adversely affected reproductive outcomes for male veterans. • Adverse effects may be attributable at least in part to increased dioxin exposures. • Results were supported for a variety of defect/disability outcomes. • Adverse effects for participants with measured dioxin likely hold more generally. • A variety of limitations may have affected these conclusions. [ABSTRACT FROM AUTHOR]

PC12 is a well studied cell model for neuronal differentiation. AChE is also considered as a marker for neuronal differentiation. In this study, we detected the change of AChE activity during the NGF induced differentiation of PC 12 cells, and targeted on the ratio of the activity of AChE on the cell surface, and found that NGF mainly increased the intracellular AChE activity. Dioxin is a kind of persistent organic pollutants which have extreme impact on human health and widely distributed all over the world. Recently, AChE was reported as a target of the toxicity of dioxin. Here we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on AChE activity in the PC12 cells, and found that at the later stage of differentiation, TCDD could decrease the AChE activity. This down regulation might not related to transcriptional regulation. [ABSTRACT FROM AUTHOR]

Exposure to Tetrachlorodibenzo- p -dioxin (TCDD) in male rats promotes, decreased sperm concentration, alterations in motility and in sperm transit time. We evaluated the effect transgenerational of in utero exposure to low doses TCDD in the sperm quality. Pregnant rats (F0) were exposed to 0.1; 0.5 and 1.0 μg of TCDD, on gestational day 15, coincides with the end of most organogenesis in the fetus. Adult male offspring (F1, F2 and F3 generation) were investigated for fertility after artificial insemination in utero . After collection of the uterus and ovaries, the numbers of corpora lutea and implants were determined. TCDD provoked alterations in sperm morphology and diminution in serum testosterone levels and sperm transit time in the cauda epididymis. The fertility significantly decreased in all the generations, at least at one dose. In conclusion, TCDD exposure decreases rat sperm quality and fertility in adult male offspring and this effects persist into the next generation. [ABSTRACT FROM AUTHOR]

6-Formylindolo[3,2-b]carbazole (FICZ) and 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) are ligands of the aryl hydrocarbon receptor (AHR) and bind to the AHR with high affinity. Until recently, TCDD was considered to be the most potent AHR agonist, but several recent studies indicate that FICZ binds with greater affinity to the AHR than TCDD. To advance our understanding of the similarities and differences of the effects of FICZ and TCDD exposure in chicken embryo hepatocyte (CEH) cultures, we compared relative expression changes of 27 dioxin-responsive genes by the use of a chicken PCR array, porphyrin accumulation and ethoxyresorufin- O- deethylase (EROD) activity at different time points. In addition, an egg injection study was performed to assess the effects of FICZ on the developing chicken embryo. The results of the current study showed: (1) mean EROD-derived relative potency values for FICZ compared to TCDD changed as a function of time (i.e. 9, 0.004, 0.0008 and 0.00008 at 3, 8, 24, and 48 h, respectively) in CEH cultures; (2) FICZ exposure did not result in porphyrin accumulation in CEH cultures; (3) concordance between gene expression profiles for FICZ and TCDD was time- and concentration-dependent, and (4) no mortality or morphological abnormalities were observed in chicken embryos injected with 0.87 ng FICZ/g egg into the air cell. The results presented herein suggest that while FICZ and TCDD share similar molecular targets, transient versus sustained AHR activation by FICZ and TCDD result in differential transcriptomic responses. Moreover, rapid metabolism of FICZ in hepatocytes resulted in a significant decrease in the induction of EROD activity. [ABSTRACT FROM AUTHOR]

In the developing mammalian brain, neural network formation is regulated by complex signaling cascades. In utero and lactational dioxin exposure is known to induce higher brain function abnormalities and dendritic growth disruption in rodents. However, it is unclear whether perinatal dioxin exposure affects the expression of genes involved in neural network formation. Therefore, we investigated changes in gene expression in the brain regions of developing mice born to dams administered 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD; dose: 0, 0.6, or 3.0 μg/kg) on gestational day 12.5. Quantitative RT-PCR showed that TCDD exposure induced Ahrr expression in the cerebral cortex, hippocampus, and olfactory bulb of 3-day-old mice. Gene microarray analysis indicated that the mRNA expression levels of Sema3b and Sema3g , which encode proteins that are known to control axonal projections, were elevated in the olfactory bulb of TCDD-exposed mice, and the induction of these genes was observed during a 2-week postnatal period. Increased Sema3g expression was also observed in the brain but not in the kidney, liver, lung, and spleen of TCDD-exposed neonatal mice. These results indicate that the Sema3b and Sema3g genes are sensitive to brain-specific induction by dioxin exposure, which may disrupt neural network formation in the mammalian nervous system, thereby leading to abnormal higher brain function in adulthood. [ABSTRACT FROM AUTHOR]

On July 10, 1976, an explosion at a chemical plant in Seveso, Italy, released up to 30 kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)—the most potent dioxin congener. Twenty years later, the Seveso Women's Health Study (SWHS) initiated a follow-up assessment of a cohort of female Seveso residents. Researchers collected serial blood, measured for TCDD levels, and recorded information about the women's medical history after the explosion. The study's aims were to: 1) modify the human PBPK model for TCDD (Emond et al. 2004; Emond et al. 2005; NCEA-USEPA, 2010) to include repetitive gestation and lactation; 2) simulate TCDD blood concentrations during different life stages including pregnancy and lactation, under different exposure scenarios; and 3) use this PBPK model to compare the influence of gestation and lactation on elimination of TCDD. After optimization of the model, it was assessed using data from the SWHS cohort. The 23 women in Subcohort A, were 4–39 years old and in Subcohort B, the 18 women were 3–17 years old when the explosion occurred. The model accurately predicted the blood concentrations during the 20 years post-exposure, including periods of pregnancy and lactation. The model was also used to analyze the contribution of gestation and lactation to the mother's elimination of TCDD. The results suggest that gestation and lactation do not significantly impact TCDD blood elimination. Future efforts will focus on using additional data to evaluate the PBPK model and improving the mathematical descriptions of lactation and multiple gestations. [ABSTRACT FROM AUTHOR]

While the U.S. EPA has issued a draft report with a 1% TCDD effective dose (ED 01 ) of 87.9 pg/kg/day based on continuous integration of key scientific evidence, a detailed and comprehensive uncertainty analysis has not been well documented. In this study, a new estimate for ED 01 was derived based on uncertainty analysis by quantitatively assessing the potential bias arising from the selection of kinetic models, dose–response models and cohorts. The cumulative serum lipid concentration (CSLC) and cumulative body burden (CBB) were reconstructed as dose metrics using a concentration- and age-dependent pharmacokinetic model (CADM), physiologically based pharmacokinetic model (PBPK), and age-dependent half-life model (FV), and the reconstructed dose metrics based on CADM and PBPK were generally higher than those based on the FV model. Three dose–response curves (linear, multiplicative and power) were used to link dose metrics and cancer risk to estimate ED 01 , and the linear model resulted in the lowest ED 01 , followed by the power model and multiplicative model, for the same cohort. Meanwhile, ED 01 based on the CADM model was the highest, followed by those based on the PBPK model and first-order model. Finally, the ED 01 was estimated to be 17.03 ± 7.83 pg/kg/day by statistically analyzing the distribution of ED 01 values based on various kinetic models, cohorts and dose–response models. The study presented here strengthens the scientific basis for understanding the potential health implications of TCDD exposure. [ABSTRACT FROM AUTHOR]

Despite the growing concern over the potential biological impact of nanoparticles (NPs) in the aquatic environment, little is known about their interactions with other pollutants. In the marine mussel Mytilus galloprovincialis, exposure to nanosized titanium dioxide (n-TiO 2 ), one of the most widespread type of NPs in use, in combination with and 2,3,7,8-tetrachlorodibenzo-p-dioxins (TCDD), chosen as model organic xenobiotic, was shown to induce significant changes in different biomarkers in hemocytes, gills and digestive gland, with distinct effects depending on cell/tissue and type of response measured. In this work, the interactive effects of n-TiO 2 and TCDD at the tissue level were further investigated in mussel digestive gland using an integrated approach transcriptomics/immunohistochemistry. Mussels were exposed to n-TiO 2 (100 μg L −1 ) and TCDD (0.25 μg L −1 ), alone and in combination, for 96 h. Transcriptomic analysis identified 48-, 49- and 62 Differentially Expressed Genes (DEGs) in response to n-TiO 2 , TCDD and n-TiO 2 /TCDD, respectively. Gene Ontology (GO) term analysis revealed distinct biological processes affected in different experimental conditions. n-TiO 2 mainly up-regulated cytoskeletal genes, while TCDD up-regulated endocrine and signal transduction related processes. Co-exposure induced transcriptional changes common to individual treatments, and identified a newly generated process, response to chemical stimulus. Transcription of selected genes was verified by qPCR. Moreover, expression of tubulin, as an example of target protein of interest identified by gene transcription data, was evaluated in tissue sections by immunolabelling. Tissue TCDD accumulation was evaluated by immunofluorescence with an anti-dioxins antibody. The results demonstrate both distinct and interactive effects of n-TiO 2 and TCDD in mussel digestive gland at the molecular and tissue level, identify the main molecular targets involved, and underline how exposure to the n-TiO 2 /TCDD mixture does not result in increased TCDD accumulation and overall stressful conditions in the tissue. These represent the first data on transcriptional responses of marine invertebrates to exposure not only to n-TiO 2 as a model of NP, but also to a legacy contaminant like TCDD. [ABSTRACT FROM AUTHOR]

The formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) was explored during de novo tests designed to compare the catalytic activity of copper (II) chloride (CuCl) with that of iron (III) oxide (FeO) and to test some synergistic effect between these two catalytic compounds. Both copper chloride (CuCl) and iron oxide (FeO) were earlier proposed as catalysts to explain the PCDD/F emissions from, e.g. municipal solid waste incineration (MSWI). In addition, haematite (FeO) is the main iron ore and could be responsible for the typical iron ore sintering plant fingerprint. A total of nine model fly ash (MFA) samples were prepared by mixing and grinding of sodium chloride (NaCl), activated carbon and a powder matrix of silica (SiO) with the selected metal compound(s). The conditions of these de novo tests were 1 h in duration, 350 °C in a flow of synthetic combustion gas (10 vol.% oxygen in nitrogen). The effect of Fe-Cu catalyst concentration on yield and distribution pattern of PCDD/F was systematically explored; three strongly differing ratios of [Fe]:[Cu] were considered (1:1, 10:1 and 100:1) to study the potential interactions of FeO and CuCl suggested earlier. The results show some slight rise of PCDD/F formed with raising iron concentration from 0 to 10.1 wt% (no Cu added; 0.1 wt% Cu), as well as strong surging of both amount and average chlorination level of PCDD/F when rising amounts of copper (0 to 1.1 wt%) are introduced. The resulting fingerprints are compared with those from sintering and from MSWI. [ABSTRACT FROM AUTHOR]

Enriched microorganisms in sediment collected from a dioxin-contaminated site in Vietnam (Bien Hoa airbase) were used for examining the effectiveness in biological treatment of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in soil. Four bio-treatments were investigated using a sequential anaerobic (17 weeks) followed by an aerobic (6 weeks) incubation. The maximum removal efficiency was approximately 60% even at an extremely low pH (approx. 3.6) condition. Surfactant Tween-80 was added to enhance the bioavailability of dioxin in two treatments, but it appeared to biostimulate methanogens rather than dechlorinators. As a result, methane production was the highest while the dioxin removal efficiency was the lowest, as compared with the other bio-treatments. Carboxymethylcellulose (CMC) coated on nanoscale zero valent iron (nZVI) surface used in two treatments could prevent the direct contact between bacterial cell surface and nZVI which prevented cell death and lysis, hence enhancing dioxin removal. The presence of CMC­­_nZVI in bio-treatments gradually released H2required for microbiological processes, but the amount used in the experiments were likely too high to maintain optimum H2levels for biostimulating dechlorinators rather than methanogens. [ABSTRACT FROM PUBLISHER]

The Bien Hoa airbase (south of Vietnam) is known as one of the Agent Orange hotspots which have been seriously contaminated by Agent Orange/dioxin during the Vietnam War. Hundreds of samples including soil, sediment and fish were collected at the Bien Hoa Agent Orange hotspot for assessment of the environmental contamination caused by dibenzo- p-dioxins and polychlorinated dibenzofurans (PCDD/Fs). The toxicity equivalency quotient (TEQ) concentration of PCDD/Fs in soil and sediment varied from 7.6 to 962,000 and 17 to 4860 pg/g dry wt, respectively, implying very high contamination of PCDD/Fs in several areas. PCDD/F levels in fish ranged between 1.8 and 288 pg/g TEQ wet wt and was generally higher than advisory guidelines for food consumption. 2,3,7,8-Tetrachlorinated dibenzo- p-dioxins (2,3,7,8-TCDD) contributed 66-99 % of TEQ for most of the samples, suggesting 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) from Agent Orange as the major source of the contamination. The vertical transport of PCDD/Fs was observed in soil column with high TEQ levels above 1000 pg/g dry wt (Vietnamese limit for necessary remediation activities- TCVN 8183:2009 ()) even at a depth of 1.8 m. The vertical transport of PCDD/Fs has probably mainly taken place during the 'Ranch Hand' defoliant spray activities due to the leaks and spills of phenoxy herbicides and solvents. The congener patterns suggest that transports of PCDD/Fs by weathering processes have led to their redistribution in the low-land areas. Also, an estimate for the total volume of contaminated soil requiring remediation to meet Vietnamese regulatory limits is provided. [ABSTRACT FROM AUTHOR]

Individuals, typically, are exposed to mixtures of environmental xenobiotics affecting multiple organs and acting through different xenosensors and pathways in species and cell-type specific manners. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and α-endosulfan are Persistent Organic Pollutants (POPs) and endocrine disruptors which act through different xenosensors and accumulate in the liver. Our objective in this HEALS study was to investigate the effects of the mixture of these POPs on gene expression in a human-derived hepatocyte cell line, HepaRG. We found that, in spite of having largely uncorrelated effects, TCDD and α-endosulfan, when mixed, alter the expression of genes. The combined effects of the mixture of the POPs significantly altered the expression of 100 genes (42 up- and 58 down-regulated) whereas the same concentration of either POP alone did not alter significantly the expression of these genes. For 32 other genes, selective inhibitory crosstalk between TCDD and α-endosulfan was observed. One of the POPs inhibited the effect, on gene expression, of the other in the mixture although, when used alone, that POP did not affect expression. The expression of another 82 genes was significantly altered (up- or down-regulated) by a single POP. The addition of the second POP either increased, in the same direction, the effect on gene expression or had no further effect. At low concentrations (0.2 nM TCDD and 1 μM α-endosulfan), the POPs still had significant effects and the levels of expression of the corresponding proteins were found to be affected for some genes. Particularly striking was the 80–90% inhibition, by the mixture, of the expression of a number of genes of several hepatic intermediary metabolic pathways (glycerolipid metabolism, FXR/RXR activation, glycolysis/gluconeogenesis, retinoid and bile acid biosynthesis), whereas each pollutant alone had only a moderate effect. [ABSTRACT FROM AUTHOR]

The lower Passaic River is an operable unit of the Diamond Alkali Superfund site at 80 and 120 Lister Avenue in Newark, New Jersey, USA. Between 1948 and 1969, the Diamond Shamrock Chemicals Company and its predecessors manufactured chemicals such as pesticides and phenoxy herbicides, including 2,4,5-trichlorophenol, which is a precursor to 2,4,5-trichlorophenoxyacetic acid, one of the primary components used to make the military defoliant Agent Orange. A by-product of this manufacturing process was 2,3,7,8-tetrachlorodibenzodioxin (2,3,7,8-TCDD), and the site is considered the dominant source of 2,3,7,8-TCDD to the lower Passaic River and its environs. Several investigators have identified the ratio of 2,3,7,8-TCDD to total TCDD as a fingerprint for the site source. The present study presents data that establish polychlorinated dibenzodioxin/polychlorinated dibenzofuran (collectively, PCDD/F) congener and homolog fingerprints of soil and sump samples from the site. It then compares those fingerprints to the PCDD/F congener and homolog patterns in lower Passaic River sediments. The similarity of the patterns in lower Passaic River sediments to the site fingerprint indicates the site is the dominant source of the 2,3,7,8-TCDD in sediments within approximately the lower 14 miles of the lower Passaic River, excluding, for the purposes of the present discussion, Newark Bay. In addition, PCDD/F congener data indicate that the ratio of 1,3,7,8-TCDD to 2,3,7,8-TCDD is another marker of the site and corroborates the findings from the other fingerprints. Environ Toxicol Chem 2015;34:1485-1498. © 2015 The Authors. Published by SETAC. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effect of tocopherol on pleuritis-induced rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Rats were treated with a single TCDD dose of 5 μg/kg body weight (b.w.) and then for 3 weeks they were daily supplemented with tocopherol at a dose of 30 mg/kg b.w. The inflammation was initiated by intrapleural injection of a single dose of 1% carrageenin solution in a volume of 0.15 ml. Changes in biochemical blood parameters were measured three times at the 24th, 72nd and 120th hour of pleuritis and the blood was collected from 20 animals of each group of rats (group with the control inflammation; group treated with TCDD and with control inflammation; group treated with TCDD, supplemented with tocopherol and with the inflammation). The following biochemical parameters were measured: tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-2, IL-4, IL-6, procollagen, telopeptide, fibrinogen, cholesterol, urea, creatinine, aspartate aminotransferase (AspAT) and alanine aminotransferase (AlAT). Daily supplementation of tocopherol caused significant changes in the level of TNF, IL-1, IL-4, IL-6, urea, creatinine, AspAT and AlAT. According to the results of these studies, we suggest that tocopherol supplementation in high doses could act as a protective treatment to improve liver metabolism. [ABSTRACT FROM AUTHOR]

Concern exists that polychlorinated biphenyls (PCBs) may be contributing to the current decline of shovelnose sturgeon ( Scaphirhynchus platorynchus) and the US federally endangered pallid sturgeon ( Scaphirhynchus albus). Waterborne exposures with newly fertilized eggs were used to assess developmental and morphological effects of 2 of the most potent aryl hydrocarbon receptor (AhR) agonists, 3,3′,4,4′,5-pentachlorobiphenyl (PCB-126) and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), on early life stage shovelnose and pallid sturgeon. No dose-related effects of PCB-126 were observed on percent development or hatch in either species at concentrations as high as 1711 ng/g egg. Effects of TCDD on percent development were not assessed in shovelnose sturgeon. However, percent development was not affected by TCDD in pallid sturgeon, and percent hatch was unaffected by TCDD doses as high as 60 ng/g egg to 81 ng/g egg in either species. Morphological pathologies such as yolk sac edema and craniofacial deformities were typical of AhR agonist exposure and were similar in both species. Calculated PCB-126 50% lethal dose (LD50, 95% fiducial limits) values were 196 ng/g egg (188-203 ng/g) for shovelnose and 159 ng/g egg (122-199 ng/g) for pallid sturgeon. Likewise, calculated TCDD LD50 values were 13 ng/g egg (11-15 ng/g) for shovelnose and 12 ng/g egg (10-14 ng/g) for pallid sturgeon. These LD50 values are among the highest recorded in early life stage fish, suggesting that early life stage Scaphirhynchus sturgeon may be comparatively insensitive to AhR agonists. Environ Toxicol Chem 2015;34:1417-1424. © 2015 SETAC [ABSTRACT FROM AUTHOR]

Establishment of the dioxins emission inventory has been considered as a crucial step toward risk assessment and elimination of dioxins contaminations. Based on a total dioxin emission inventory in China from different emission categories in 2004, this study created a gridded emission inventory of 2,3,7,8-TCDD, the most toxic congener in dioxins, in China in 2009 with a 1/4° longitude by 1/4° latitude resolution. It was estimated that annually total 371 ± 53 g (average ± standard deviation) of 2,3,7,8-TCDD was released into the atmosphere in 2009 over China, increasing approximately by 37% compared with its emission in 2004. Differing from most developed countries where municipal waste incinerations were regarded as a major atmospheric emission source, in China ferrous and non-ferrous metal production made the largest contribution to 2,3,7,8-TCDD air emission (138 ± 16 g), followed by waste incineration (109 ± 12 g), power and heating generation (62 ± 9 g), and production of mineral products (47 ± 8 g). The rest of sources contributed approximately 3% to the total 2,3,7,8-TCDD emission in 2009. Iron and steel industries are mainly located in Beijing–Tianjin–Hebei (BTH) and Yangtze River Delta (YRD) regions, whereas waste incinerators are mainly located in Pearl River Delta (PRD) region. Higher 2,3,7,8-TCDD emissions were found in these three regions. While the BTH, YRD, and PRD accounted for only about 4% of total land area of China, they contributed approximately 14%, 15%, and 5% to the total 2,3,7,8-TCDD emission in 2009 in China, respectively. [ABSTRACT FROM AUTHOR]

DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood. Hence, we tested the hypothesis that developmental exposure to TCDD affects dnmt gene expression patterns. Zebrafish embryos were exposed to 5 nM TCDD for 1 h from 4 to 5 h post-fertilization (hpf) and sampled at 12, 24, 48, 72, and 96 hpf to determine dnmt gene expression and DNA methylation patterns. We performed a detailed analysis of zebrafish dnmt gene expression during development and in adult tissues. Our results demonstrate that dnmt3b genes are highly expressed in early stages of development, and dnmt3a genes are more abundant in later stages. TCDD exposure upregulated dnmt1 and dnmt3b2 expression, whereas dnmt3a1 , 3b1 , and 3b4 are downregulated following exposure. We did not observe any TCDD-induced differences in global methylation or hydroxymethylation levels, but the promoter methylation of aryl hydrocarbon receptor (AHR) target genes was altered. In TCDD-exposed embryos, AHR repressor a ( ahrra ) and c-fos promoters were differentially methylated. To characterize the TCDD effects on DNMTs, we cloned the dnmt promoters with xenobiotic response elements and conducted AHR transactivation assays using a luciferase reporter system. Our results suggest that ahr2 can regulate dnmt3a1, dnmt3a2 , and dnmt3b2 expression. Overall, we demonstrate that developmental exposure to TCDD alters dnmt expression and DNA methylation patterns. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) is the most toxic congener of the polyhalogenated aromatic hydrocarbons (PAH), which causes anatomical abnormalities and developmental defects, impairs ovulation and reduces fertility. TCDD's endocrine-disrupting effects are, in part, caused by a direct action at the ovary. Herein we investigated the in - vitro effects of environmentally relevant doses of TCDD on estradiol-17β (E 2 ) production by human luteinizing granulosa cells (hLGC) obtained from women stimulated for in - vitro fertilization (IVF). TCDD at all concentrations tested (3.1 fM, 3.1 pM and 3.1 nM) significantly decreased E 2 secretion when assayed for by radioimmunoassay (RIA). Herein we confirm that TCDD alters E 2 secretion by hLGC in a time-, not dose-dependent fashion and are the first to show decreases in E 2 secretion with fM concentrations of TCDD. Using real-time quantitative PCR (RT-qPCR), the decreased E 2 secretion correlates with a decrease in the mRNA expression levels two enzymes in the estrogen biosynthesis pathway: CYP11A1 and CYP19A1 . [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCCD) is one of the most dangerous compounds that infect the environment and hence its removal is crucial for safety in human life. In this work, we have investigated the interaction of TCDD with boron nitride nanotubes (BNNTs) and carbon nanotubes (CNTs) by using the density functional theory (DFT) calculations. Our first-principles results have been validated by experiment and also other theoretical values for the similar system. The adsorption energies for TCDD molecule on the BNNTs and CNT are calculated. It was found that TCDD adsorption ability of BNNT is slightly stronger than that of CNT and TCDD molecule prefers to be adsorbed on BNNTs with molecular axis parallel to the tube axis. The results obtained indicate that TCDD is weakly bound to the outer surface of all the considered nanotubes and the obtained adsorption energy values and binding distance are typical for the physisorption. We also evaluated the influence of curvature and introduced defects on the TCDD adsorption ability of BNNTs. Furthermore, we have analyzed the electronic structure and charge population for the energetically most favorable complexes and the results indicate that no significant hybridization between the respective orbitals of the two entities was accomplished. [ABSTRACT FROM AUTHOR]

Agent Orange (AO) was the main defoliant used by the US in Vietnam from 1961 to 1971; AO was contaminated with dioxin (2,3,7,8-tetrachlorodibenzo- p -dioxin, or TCDD). Three major dioxin “hot spots” remain from previous AO storage and use at former US bases at Bien Hoa, Da Nang, and Phu Cat, posing potential health risks for Vietnamese living on or near these hot spots. We evaluated potential risk factors contributing to serum TCDD levels in Vietnamese residents at and near contaminated sites in Da Nang and Bien Hoa, Vietnam. We used multiple linear regression to analyze possible associations of blood dioxin concentrations with demographic, socioeconomic, lifestyle, and dietary risk factors for residents living on or near these hot spots. For the Da Nang study, fish farming on the site, living on property flooded from monsoon rains, and age were among the factors showing significant positive associations with serum TCDD concentrations. For the Bien Hoa study, fish farmers working at this site and their immediate family members had significantly higher serum TCDD concentrations. Our results suggest that water-related activities, especially fish-farming, at the hot spots increased the risk of exposure to dioxin. [ABSTRACT FROM AUTHOR]

To inform risk assessment and regulatory decision-making, the relationship between 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) and prostate cancer requires clarification. This article systematically and critically reviews the epidemiologic evidence on the association between exposure to TCDD or Agent Orange, a TCDD-contaminated herbicide used during the Vietnam War, and prostate cancer risk. Articles evaluated include 11 studies of three cohorts, four case-control or cross-sectional studies, and three case-only studies of military veterans with information on estimated Agent Orange or TCDD exposure; 13 studies of seven cohorts, one case-control study, and eight proportionate morbidity or mortality studies of Vietnam veterans without information on Agent Orange exposure; 11 cohort studies of workers with occupational exposure to TCDD; and two studies of one community cohort with environmental exposure to TCDD. The most informative studies, including those of Vietnam veterans involved in Agent Orange spraying or other handling, herbicide manufacturing or spraying workers with occupational TCDD exposure, and community members exposed to TCDD through an industrial accident, consistently reported no significant increase in prostate cancer incidence or mortality. Only some potentially confounded studies of Vietnam veterans compared with the general population, studies with unreliable estimates of Agent Orange exposure, and analyses of selected subgroups of Vietnam veterans reported positive associations. Overall, epidemiologic research offers no consistent or convincing evidence of a causal relationship between exposure to Agent Orange or TCDD and prostate cancer. More accurate exposure assessment is needed in large epidemiologic studies to rule out a causal association more conclusively. [ABSTRACT FROM AUTHOR]

Highlights: [•] In vitro and in vivo interactive effects of n-TiO2 and TCDD are reported in mussel. [•] Both synergistic and antagonistic effects were observed on a wide range of biomarkers. [•] Exposure to of n-TiO2increased TCDD accumulation, indicating a Trojan horse effect. [ABSTRACT FROM AUTHOR]

Highlights: [•] A new immunohistochemical method was developed to detect B[a]P and TCDD in worms. [•] Cryostat sections of E. andrei were reacted with antibodies for PAHs and dioxins. [•] Immunofluorescence was observed even at minimal concentrations of the test chemicals (ppb). [•] The gut has proved to be the major route of toxicant absorption in exposed organisms. [•] Double immunolabelling demonstrated the lysosomal accumulation of the test chemicals. [Copyright &y& Elsevier]

World Health Organization (WHO) toxic equivalency factors are used to calculate toxic equivalent (TEQ) concentrations of complex mixtures of dioxin-like compounds (DLCs), such as polychlorinated dibenzo- p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls (PCBs), for mammals, fish and birds. The TEQ concept assumes that all species of a taxa respond with similar sensitivity to individual DLCs, but several reports do not support this assumption for birds. Our laboratory is conducting research to attempt to uncover the fundamental mechanism(s) underlying the reasons why avian species differ in sensitivity to DLCs. The present study determined concentration-dependent effects of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) on ethoxyresorufin- O-deethylase (EROD) activity in primary cultures of northern bobwhite quail ( Colinus virginianus) hepatocytes. Bobwhite quail were studied because (1) this species is used in the laboratory for toxicity testing and (2) the amino acids at all locations within the ligand binding domain (LBD) of aryl hydrocarbon receptor 1 (AHR1) in bobwhite quail and ring necked pheasant ( Phasianus colchicus) are identical. Because earlier work indicated the importance of the identity of amino acids at key sites within the AHR1 LBD, we hypothesized that bobwhite quail and ring necked pheasant hepatocytes should have similar sensitivity to EROD induction by DLCs. EC-based relative sensitivity of the bobwhite quail compared to chicken for TCDD, PeCDF and PCB 126 was 0.11, 0.17 and 0.02, respectively. The rank order of potency was PeCDF > TCDD > PCB 126. The results confirm that bobwhite quail and ring-necked pheasant hepatocytes have similar sensitivity to EROD induction by TCDD, PeCDF and PCB 126. [ABSTRACT FROM AUTHOR]

A physiologically-based pharmacokinetic model was developed for the disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) in 2 fish species-fathead minnow and medaka. The model was developed based on the empirical data on disposition of dioxins in fish tissues, as well as existing knowledge on the mechanisms of uptake, distribution, storage, and elimination of dioxins in various species (other than fish). The present study examined the applicability of mechanisms known to occur in other species for fish and concluded that the same mechanisms defined for disposition of 2,3,7,8-TCDD in (mostly) rodents can be applicable for the 2 fish species examined as well. Parameter values for the model were selected and/or calibrated using available databases. Model compartments included the gill, kidney, liver, and other richly-perfused tissues, as well as fat and other slowly-perfused tissues. The model was calibrated using 2 independent datasets for exposure of fathead minnow and medaka to 2,3,7,8-TCDD in water. The initial values of the model parameters were selected from several sources, and calibrated to represent the 2 exposure datasets. With very few exceptions, the estimated parameter values for the 2 species were comparable, and the final predictions were in strong agreement with the observations. The model developed in the present study can therefore be used in the prediction of the body burden of 2,3,7,8-TCDD in fathead minnow and medaka. Uncertainty in the model prediction as a result of variability in input parameters is discussed for the parameters with the highest impacts on the model outcome. Environ Toxicol Chem 2014;33:1064-1071. © 2014 SETAC [ABSTRACT FROM AUTHOR]